Foremost among the pathogens under study in this new project is the influenza virus, including both the agents of conventional seasonal influenza as well as the emerging threat of avian (H5N1) virus. Novel means to treat infection with either agent using existing or newly developed strategies are a primary focus of this important new project within the Clinical Research Section of the LIR. The first major initiative undertaken in this project has been a collaborative protocol undertaken with the Department of Veterans Affairs (DVA) as well as the Department of Defense. The goal of this multi-center protocol was to determine if novel pharmacokinetic means could be used to extend the useful half-life of oseltamivir, the major licensed oral antiviral drug used to treat seasonal influenza in the United states and elsewhere and also a drug in comparatively short supply on a global scale. Specifically, the protocol examined the effect of two different doses of oral probenecid, a licensed uricosuric agent known to affect the renal secretion of certain drugs, on the relative pharmacokinetics of conventional prophylactic doses of oral oseltamivir administered every other day compared to daily oral oseltamivir alone. This protocol was conducted in 53 normal volunteers above and below 65 years of age at 4 centers in the United States: two DVA sites (including the Palo Alto Health Care system as lead center), one DOD site, and the NIH Clinical Center. The pharmacokinetics of oseltamvir plus probenecid were analyzed and showed a dose-dependent favorable effect of the latter upon both the trough and area-under-the-curve concentrations of the former. At the schedule of four times daily dosing with probenecid, these parameters were not statistically different from daily dosing of oseltamivir alone, suggesting that probenecid might be useful in extending the supply of oseltamivir in a situation of limited drug supply.[unreadable] The ability of oseltamivir to treat effectively severe cases of seasonal influenza may be limited, and knowledge of its utility in treating human cases of avian influenza is largely anecdotal. For these reasons we undertook three clinical trials focused on the therapeutics of human influenza. One is a phase II double-blinded, randomized clinical trial conducted within a network of research collaborators in Southeast Asia that is comparing the relative efficacy of high dose versus standard-dose oseltamivir for the treatment of severe influenza and avian influenza. This trial is presently still accruing in the affected countries. The second was a phase I double-blind, placebo-controlled, dose-escalating study to evaluate the relative safety and tolerability of a novel intravenous anti-influenza agent, peramivir, in healthy volunteer subjects. This trial was initiated at the Clinical Center but then largely completed by the sponsor through a Clinical Research Organization. Data from that trial are presently being analyzed and prepared for publication. The third trial is a phase II vaccine dose-finding pilot study for the development of an anti-influenza A (H5N1) intravenous hyper-immune globulin preparation of potential utility in the treatment of human cases of avian influenza. The primary objective of this trial was to determine the optimal vaccination strategy to achieve high titer anti-influenza H5N1 antibodies in healthy volunteers using the licensed H5NI vaccine. Four cohorts were enrolled: the first three (n= 75 volunteers) received four doses of either 90, 120, or 180 micrograms of H5N1 vaccine over several months, whereas the fourth cohort (n= 51 volunteers) received two doses of 180 micrograms. Data from all cohorts are still being analyzed, but preliminary findings are that 1) hyper-immunization with H5N1 vaccine is safe, and 2) comparatively high titer (titer of 1:80 or greater) immune globulin can be raised in a relatively high percentage of recipients, but optimization of vaccine dose versus frequency of administration might still need further study.[unreadable] In addition to these trials, we have also undertaken a study of a novel nasally-administered agent with potential antiviral activity against a variety of respiratory viruses, including influenza. In this phase I double-blind, placebo-controlled, dose-escalating study to evaluate the safety and tolerability of topical nasal Poly-ICLC (synthetic dsRNA strands of poly-inosinic and poly-cytidylic acids), normal volunteers are receiving escalating doses of this biologic response modifier to determine its safety when nasally administered as well as to measure both local and systemic immunologic effects of its administration. This trial is currently accruing and final data analysis is anticipated to begin within the next 6-8 months.[unreadable] Lastly, in addition to the clinical trials described above, we continue to monitor on a yearly basis the clinical and psychologic status and well-being of a subset of patients previously exposed to anthrax as a result of the October 2001 anthrax attack,[unreadable] as well as maintaining an open clinical protocol for the study of additional anthrax exposures that may occur through accidental or occupational exposures.